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M.D. Berger et al.
vi) whether the majority had advanced stage, and vii) whether the majority had bulky disease. As shown in Figure 5, we failed to explain between-trial heterogeneity by stratifying on any of these subgroups.
Discussion
We here provide a large and comprehensive meta- analysis with the best currently available data from ran- domized trials on consolidation radiotherapy in the first- line treatment of aggressive lymphomas. In summary, we find no evidence for a survival benefit of an unselected consolidation radiotherapy for these patients, but uncer- tainty remains high.
Our analysis extends the data from both retrospective and uncontrolled series in favor2,23-25 or against26 the use of consolidation radiotherapy in the first line setting. Our state-of-the art and updated meta-analysis that takes into account general concerns on the reproducibility of meta- analysis8,9 and significantly corroborates a previous meta- analysis on a limited number of trials.27 It also goes beyond extrapolations from data on particular extranodal sites,28 the common use of consolidation radiotherapy for
limited clinical stages only,23 pretreatment with different chemotherapy,29 or to treat bulky disease only.2 Collectively, the latter data are the basis for the current recommendations on the combined treatment modality also for patients with advanced stages. They have created an unsatisfactory uncertainty and rely on experts’ opin- ions on the use of radiotherapy when facing an individual patient. However, DLBCL is a disease in which cure, but also treatment-related toxicities and economic factors have to be considered. Unfortunately, our meta-analysis cannot provide data on costs, safety and long term risks of secondary malignancies related to radiation therapy.
Overall, the data that could be used for this meta-analy- sis is of mixed quality (Tables 1 and 2). As an extreme, three of the four randomized trials by the same group all clearly supporting the added value of radiotherapy have later been retracted, the last one in early 2019.14-16 We dis- play their results in our figures as they might have influ- enced the use of consolidation radiotherapy in routine practice or clinical trials before their retraction. The results of the important UNFOLDER trial is still not fully published.17,22 The trials used for this meta-analysis also harbor considerable conceptual heterogeneity: radiother- apy was given to shorten chemotherapy and its toxicity,
Table 1. Summary on the randomized trials used for the meta-analysis. The number of patients in the respective column indicates the actual number of patients for the individual trials that received consolidation radiotherapy in a randomized fashion. The retracted trials are highlighted in grey. The superscript number in the study column refers to the number of the references in the manuscript.
Trial
(with reference)
Aviles et al.13 Engelhard et al.18 ECOG 148419 Avileset al.14 SWOG 8736 20 GELA 93-111 GELA 93-412 Aviles et al.15 Aviles et al.16 UNFOLDER17,22 GOELAMS 02 0321
Diagnosis
DLCL
high grade NHL
diffuse aggressive NHL DLCL intermediate & high grade NHL aggressive NHL aggressive NHL
PMBL
DLBCL
Largely DLBCL
DLBCL
Patients (#)
218
110 (of 548) 172 (of 399) 341
401 (of 442) 318 (of 647) 576
124 (of 182) 258 (of 612) 285
334
Recruitment period
1983-1988
1986-1989 1984-1992 1989-1995 1988-1995 1993-2000 1993-2002 2001-2004 2006-2010 2005-2012 2005-2013
Mean age (y)
59-61
56
59 53-57 59 46-47 68-69 32-35 53 44 56
Bulky disease
all
Same Rituximab chemotherapy used
Radiation dose >30 Gy
yes
yes no yes yes yes yes no no yes yes
only CR and bulky disease
only CR pts
only CR pts
only CR and bulky disease
all
all
all
only CR pts
only CR and bulky disease
initially 4 arms; random
for RT only in CR pts.
random at start, some PR pts.
received RT
in both arms
yes
yes yes yes no no yes yes yes no yes
no
no no no no no no yes yes yes yes
Trial Publication Stages
Randomized
Aviles et al.13 Engelhard et al.18 ECOG 148419 Aviles et al.14 SWOG 873620 GELA 93-111 GELA 93-412 Aviles et al.15 Aviles et al.16 UNFOLDER17,22
GOELAMS 02 0321
Int J Radiat Biol 1994
Ann Oncol 1991
J Clin Oncol 2004
Leuk Lymphoma 2004
New Engl J Med 1998
New Engl J Med 2005
J Clin Oncol 2007
Int J Radiat Biol 2012
Hematology 2018
(12-ICML;a122);
ASCO 2018;a7574 Blood 2018
advanced
localized & advanced localized advanced localized localized localized localized advanced localized & advanced
localized
19% initially; bulky not randomized 31% initially (tumor > 10cm) all
number unknown, some initially 12% of RT pts.; 10% of non-RT pts 9% of RT pts; 8% of non-RT pts. 94% of RT pts.
30 % of RT pts.
76 % initially
for non-bulky disease only
NHL: non-Hodgkin lymphoma; DLBCL: diffuse large B-cell lymphoma; CR: complete response; pts: points; RT: radiotherapy; y: years.
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